About 5% of adults suffer from the obstructive sleep apnea syndrome (OSAS). OSAS patients have predisposing upper airway anatomy that requires increased levels of activity in those muscles that maintain the upper airway open. Sleep-related decrements of that activity result in intermittent upper airway obstructions, sleep loss, impaired alertness, hypertension and metabolic disorders. Endogenous noradrenergic (NE) drive determines the level of activity in hypoglossal (XII) motoneurons (mns) that innervate the genioglossus, a muscle that plays a key role in the maintenance of upper airway patency in OSAS. This drive originates in neuronal groups that have decrements of activity during sleep and from one NE group that our recent data suggest is not state-dependent, the medullary A1 group. We hypothesize that the A1 group contributes to the increased levels of activity in upper airway muscles during wakefulness, a well established adaptation in OSAS that may be caused by the chronic-intermittent hypoxia(CIH) that OSAS patients experience as a result of the disorder. Another important source of wake-related excitation of XII mns is the posterior, lateral hypothalamus. This excitation is thought to originate in the neurons that synthesize the peptide orexin (ORX) and is believed to be relayed to mns by brainstem NE neurons. However, we found that aminergic pathways are not required. This leads us to hypothesize that hypothalamic excitatory input to XII mns is mediated by direct projections of ORX neurons to the XII nucleus or by non-aminergic pontomedullary XII-premotor neurons. To address these hypotheses, we propose four Specific Aims. (1) Determine the magnitude of the excitatory drive to XII mns that originates in NE XII-premotor neurons of the A1 group. In urethane-anesthetized rats, we will measure the effect of silencing of these neurons on XII nerve activity. We will also record from A1 XII-premotor cells to determine whether their activity is altered during pharmacologically induced REM sleep-like state. (2) Determine whether the activity of A1 neurons is increased in rats exposed to chronic-intermittent hypoxia (CIH), whether there is a concomitant increase of catecholaminergic markers in the ventrolateral medulla and increased density of NE terminals in the XII nucleus. (3) Determine whether CIH increases the magnitude of the excitatory drive to XII mns from the A1 region and increases expression of the excitatory a -adrenergic receptors in the XII nucleus. (4) 1 Determine whether the wake-related excitatory drive to XII mns that originates in ORX neurons is mediated by their direct projections to the XII nucleus or by XII-premotor neurons with ORX receptors. We will pharmacologically activate ORX neurons and antagonize ORX receptors in the XII nucleus while measuring XII nerve activity and examine Fos expression in pontomedullary XII-premotor neurons following stimulation of ORX neurons with and without systemic antagonism of ORX receptors. Thus, we will characterize two major sources of excitatory drive to XII mns and assess the impact of CIH on one of these inputs. This will advance our understanding of the mechanisms leading to altered by OSAS control of the upper airway. PUBLIC HEALTH RELEVANCE: About 5% of adults suffer from the obstructive sleep apnea syndrome (OSAS), a disorder that causes sleep loss and fragmentation, impaired alertness, arterial hypertension and metabolic disorders. We plan to use a rodent model to study the neural pathways responsible for increased activity in the muscles that keep the airway open in OSAS patients and to determine whether chronically occurring decrements of blood oxygen levels, like those experienced by OSAS patients, alter the central neural control of the upper airway. This should help understand the pathophysiology of OSAS and identify potential therapeutic targets.